Inverse agonism and the regulation of receptor number.
Inverse agonists are ligands that preferentially stabilize inactive conformations of G protein-coupled receptors. In a range of systems, sustained treatment with inverse agonists can produce substantially greater upregulation of receptor levels than antagonists. The use of constitutively active mutant receptors can exaggerate this effect but may also allow agonists and antagonists to mimic the effect by preventing denaturation of the mutant receptor polypeptide. In this review Graeme Milligan and Richard Bond consider the basis for these effects and their therapeutic implications.
Milligan
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Division of Biochemistry and Molecular Biology, University of Glasgow, UK.
Bond
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RA
D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D017442:Histamine Agonists / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D011487:Protein Conformation; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics; D043562:Receptors, G-Protein-Coupled; D011970:Receptors, Histamine H2 / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; C097350:GPR12 protein, human; C486281:GPR68 protein, human; D017442:Histamine Agonists; D006633:Histamine Antagonists; D018343:Receptors, Adrenergic, beta-2; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D011970:Receptors, Histamine H2; D019204:GTP-Binding Proteins